Insecticidal biodegradable methylthio analogs of ddt

ABSTRACT

WHERE R and R&#39;&#39; are different and R is selected from the group consisting of -CH3, -CH3O, -C2H5O, -C3H7O, and R&#39;&#39; is selected from the group consisting of -SCH3, and -CH3; and methods for providing and selectively controlling the biodegradability of DDT analogue insecticides.   Asymmetrical, biodegradable insecticides having the formula:

United States Patent Metcalf et al.

[ Dec. 17, 1974 INSECTICIDAL BIODEGRADABLE METHYLTHIO ANALOGS OF DDTInventors: Robert L. Metcalf; Inder Kapoor;

Asha Hirwe, all of Urbana, Ill.

Assignee: University of Illinois Foundation,

Urbana, Ill.

Filed: Sept. 6, 1973 Appl. No.: 394,567

Related US. Application Data Division of Ser. No. 147,247, May 26, 1971,Pat. No. 3,787,505.

US. Cl 260/609 E Int. Cl. C07c 149/30 Field of Search 260/609 E, 609 FReferences Cited UNITED STATES PATENTS l/l974 Metcalf et al. 260/609 FPrimary ExaminerLewis Gotts Assistant Examiner-D. R. Phillips Attorney,Agent, or Firm-Merriam, Marshall, Shapiro 81. Klose 5 7] ABSTRACTAsymmetrical, biodegradable insecticides having the formula:

2 Claims, No Drawings INSECTICIDAL BIODEGRADABLE METI-IYLTHIO ANALOGS OFDDT This is a division of application Ser. No. 147,247, filed May 26,1971 now US. Pat. No. 3,787,505.

SUMMARY OF THE INVENTION wherein R and R are different and R is selectedfrom tl e group consisting of CI-I Cl-I O, --C I-I O,

insecticides,

BACKGROUND OF THE INVENTION Despite the immense utility of DDTl,l,l-trichloro- 2,2-bis(p-chlorophenyl)ethane as an insecticide, itsusefulness is prejudiced by its environmental stability and low degreeof biodegradability. There is growing concern about the continuingliberation of vast quantities of DDT into the environment. The veryqualities which make DDT such an effective contact or residualinsecticide (its stability, very low water solubility and high lipidsolubility) result in its accumulation in the fatty or lipid tissues ofanimals and are responsible for its ecological manification incarnivorous animals at the upper ends of food chains. The problems ofthe biological accumulation of DDT are intensified by its enzymaticmetabolic conversion to the even more stable dehydrochlorinationproduct, DDE, l,l-dichloro-2,2- bis-(p-chloro-phyenyl)ethylene, which isamajor environmental pollutant.

The drug metabolizing or multifunction oxidase (MFO) enzymes are knownto play a dominant role in determining the absolute toxicity ofinsecticides to both insects and higher animals. DDT and its metabolicderivatives DDE and DDD (or TDE), l,l-dichloro 2,2- bis-(p-chlorophenyl)ethane are all highly resistant to detoxication by MFO enzymes and thissingle factor accounts for their storage and accumulation in animaltissues, especially at the higher ends of food chains. On the otherhand, certain known symmetrical DDT analogues such as methoxychlor, l,l,l-trichloro-2,2-bis-(p methoxyphenyl)ethane and methiochlor,l,l,ltrichloro 2,2-bis-(p methiophenyl)ethane, are readily attacked byMFO enzymes which metabolically convert or biodegrade such analogues,into environmentally acceptable products, rapidly eliminated by animals.Thus, methoxychlor is an example of a persistent but biodegradableinsecticide which does not generally accumulate in animal tissues and isa more prudent choice than DDT for a variety of uses where environmentalpollution is an important factor. However, methoxychlor and other knownsymmetrical DDT analogues (e.g., methylchor, l,l,l-trichloro-2,2-bis (pmethylphenyl)ethane or methiochlor) While exhibiting satisfactoryinsecticidal activity toward certain species of insects, exhibitconsiderably less insecticidal activity than DDT towards other speciesof insects. Thus, there exists a need for improved, persistentinsecticides which manifest insecticidal activity levels aboutcomparable to DDT, but which can also be metabolically biodegraded so asto prevent their accumulation in animals, particularly vertebrata, e.g.birds, fish and mammals.

DESCRIPTION OF THE INVENTION We have found from metabolic studies ininsects, mice, and in a model ecosystem with several food chains thatcertain asymmetrical DDT analogues with substituent groups readilyattacked by multifunction oxidase (MFO) enzymes are substantiallybiodegradable and do not appear to be stored readily in animal tissuesor concentrated in food chains. Insecticidal activity studies involvingflies and mosquitoes have further indicated that the DDT analogues ofthis invention are persistent, biodegradable insecticides, of very lowmammalian toxicity. The present invention thus provides compositionswhich are effective and persistent insecticides in-inanimate situations;yet, when such compositions are absorbed into living organisms theycontain one or more points readily suceptible for attack by the MP0enzymes, promoting rapid detoxication of the insecticide. Suchcompositions have many advantages as safe, relatively stable, andpotentially inexpensive residual insecticides. As employed herein theterms DDT analogue or DDT type are used synonymously to meaninsecticides which comprise p-p disubstituted diaryl trichloroethanes.The asymmetrical DDT analogues of the present invention contain at leastone p-substitutent group such as methoxy (*Cl'l O), methio (-SCI-l ormethyl (CH;,) which in the presence of MP0 enzymes acts as a substratefor MFO enzymes and thereby biodegrades or metabolically converts suchanalogues into environmentally acceptable products. The compositionsalso contain a second, different, psubstituent group which at least inpart contributes to the insecticidal activity and/or the relatively lowmammalian toxicity exhibited by the compositions of the presentinvention and may also contribute to their biodegradability.

We have further found that the asymmetrical DDT analogues having thefollowing formula, and believed to be new compositions, are highlyinsecticidal, yet biodradable when contacted by MFO enzymes and thus oflow toxicity to mammals:

where R and R are different and R is selected from the group consistingof CI-I CH O, C H O, C H 0 and R is selected from the group consistingof SCH and -CH The preparation or synthesis of the asymmetrical DDTanalogues of the present invention can be accomplished by Bayer orFriedel Crafts condensation reactions between chloral and theappropriate substituted benzenes, for example, toluene, thioanisole,alkoxybenzenes, etc. The following Example I will illustrate thepreparation of 2-(p-methoxyphenyl)-2-(pmethylthiophenyl )-l ,l,l-trichloro ethane.

EXAMPLE I To 100 ml. of chloroform in an erlenmeyer flask cooled at 4 C,was added 5.32 g. (0.04 mole) of anhydrous AlCl The contents of theflask were stirred for 10 minutes and a mixture of 10.2 g.p-methoxyphenyll,l,l-trichloro-methyl carbinol (U.S. R2, 719, 865 Oct.4, 1955), 7.5g. of thioanisole, and 25 ml. of chloroform, was addeddropwise over 10 minutes. The contents were stirred for a further 5minutes, allowed to come to room temperature and stirred overnight. Themixture was then poured over an ice-HCl mixture, steam distilled for onehour to remove chloroform and unreacted thioanisole, extracted withdiethyl ether, and dried over anhydrous Na SO Evaporation of the ethergave 14.5 g. (95%) yield of 2-(p-methoxyphenyl)-2-(pmethylthiophenyl)-l,l l-trichloroethane, which after two recrystallizations from boilingmethanol gave Compositions of the present invention were tested forinsecticidal activities determined by standard methods, and comparedwith the activities of DDT and other symmetrical analogues of DDT, e.g.methoxychlor. In these tests, female house flies. Musca domestica, underCO anesthesia, were treated with topical application of 1 ul drops ofw/v solutions of the insecticides in acetone. Three replicates of 20flies 2-4 days old were treated on the pronotum at each dosage, and atleast 5 dosages were used to establish each dosage versus mortalitycurve. Mortalities were determined by holding the flies at 72 F. (22 C.)with sucrose solution as food. Topical applications were made to bothsusceptible (SNAlDM) and DDT-resistant (Rsp) strains in exactly the samemanner. The results of these evaluations are reported in Table II as LDvalues in ug. of toxicant per gram of insect using the average weight ofthe house fly as 20 mg. Evaluations of the toxicity of the samecompositions to the larvae of the mosquitoes Culex pipiensquinquefasciatus and Anopheles albimanus were made as described by WHOmac/19st) tldthstss lt are also shown I b l TABLE ll Comparison ofToxicity of New Unsymmctn'cal DDT Analogues to DDT and Methoxychlorwhite, pleasant smelling crystals m.p. 94 C. NMR showed CH S protons at7.55T., Cl-l O protons at 6.20T, -H at 5.02T.-fully confirming thestructure. Using techniques similar to those employed in Example I theother compositions shown in Table l were prepared.

The results shown in Table ll indicate that the exemplified compositionsof the present invention are all more active than methoxychlor withrespect to susceptible houseflies and all of said compositions areconsiderably more active than DDT with respect to DDT- resistanthouseflies. Moreover, the compositions of the present invention areshown to be, in general, comparable to or more active than DDT and/ormethoxychlor with respect to mosquito larvae.

Mammalian toxicity studies of the compositions of the present inventionwere conducted with female Swiss mice, six to eight weeks old. In thesestudies compositions were dissolved in olive oil at 5 to 10% w/v and therequisite dosage administered orally by a micrometer driven Hamiltonsyringe. The mice were observed for symptoms of intoxication and formortality over a one week period. The results of these studies are shownin Table III.

TABLE III MOUSE TOXICITY Com- Oral LD mg/g. pound DDT 200 Example 1 1000Example 11 1000 Example 111 1000 Example IV 1000 Example V 500 Theresults in Table III indicate that the exemplified compositions of thepresent invention are less toxic than DDT with respect to oraladministrations to mice. These studies further indicated thatcompositions containing a single methoxy, methyl, or methylthio groupare of low mammalian toxicity but nevertheless highly insecticidal,making such compositions selectively insecticidal. It is believed thatthis selective insecticidal activity is a result of the generally higherconcentration of MP0 enzymes found in mammals as compared to insects.

MODEL ECOSYSTEM A model ecosystem with several food chains was developedand can be used for evaluating pesticide biodegradability. The modelconsists of a X 12 X 18 in. glass aquarium containing a shelf of kg. ofwashed white quartz sand which is molded into a sloping soilair-waterinterface. The lower portion is covered by 12 liters ofstandardreference water" which provides satisfactory mineral nutrition for thegrowth of Sorghum halpense on the aerial portion, and the algaeOedogonium cardiacum in the aquatic portion. The latter is seeded with acompliment of plankton, and contains Daphnia magna and Physa snails. Theaquarium is provided with aeration and is kept in an environmental plantgrowth chamber at 80 F (26 C) with 12 hr daylight exposure to 5,000ft-candles.

ln operation, the Sorghum seeds are planted and the aquarium allowed toequilibrate for 20 days until the Sorghum plants are about 6 in. high.The leaves are then treated with 5.0 mg. of the radiolabeled pesticidecompound of interest in acetone applied through a micropipette so thatonly the plant surface is contaminated. Ten large Estigmene acrea larvaeare placed in the chamber and allowed to feed until the plants areconsumed. The radiolabeled fecal materials thoroughly contaminate theaqueous portion and are taken up into the several food chains. After 26days, 300 Culex quinquefasciams mosquito larvae are added to thechamber, and after 30 days three Cambusia affinis fish are added.

The experiment is terminated after 33 days, when weighed samples offish, snails, mosquito larvae, algae, and water are removed and assayedto total radioactivity. These samples are homogenized and extracted withdiethyl ether, and both water and ether layers examined by tlc todetermine the qualitative and quantitative nature of the degradativeproducts present, using radioautography and serial scintillationcounting of the areas containing radioautography. The results of thetotal examination of the model eco system provide evidence of therelative biodegradability of the pesticide. Using such a model ecosystemwith DDT as the pesticide confirms that DDT is not biodegradable butrather, manifests a substantial magnification of concentration in thefood chain organisms. In contrast, when p-p disubstituted diaryltrichloroethane insecticides which contain at least one p-substituentgroup readily susceptible to attack by MFO enzymes (e.g. -CH CH O, SCHare evaluated in the model they are found to be biodegradable in thatthere is little or no magnification of concentration of suchinsecticides in the food chain organisms.

The compositions of the present invention can be formulated intoinsecticidal formulations using techniques known in the art, forexample, in formulating DDT insecticides. Thus, dusts, waterdispersions, emulsions and/or solutions can be formulated provided thecarrier or solvent is compatible and inert in the sense that it does notreact or interfere with the insecticidal and biodegradablecharacteristics.

While the present invention has been described by reference toillustrative examples various modifications will be apparent to thoseskilled in the art and any such modifications are intended to be withinthe spirit and scope of the invention as defined by the appended claims.

What is claimed is:

1. Asymmetrical, biodegradable insecticides having the formula:

where R and R are different and R is selected from the group consistingof -CH CH O, -C H O, -C H O, and R is SCH 2. An insecticide as definedby claim 1 where-in R is --CH;,.

1. ASYMMERTICAL, BIODEGRADABLE INSECTICIDES HAVING THE FORMULA:
 2. Aninsecticide as defined by claim 1 where-in R is -CH3.